Technical Field
The present invention generally relates to compositions used for expanding cells and for treatment of disorders using gene therapy. More particularly, the present invention relates to improved gene therapy compositions for expanding hematopoietic cells and related methods for treatment of diseases, disorders, and conditions of the hematopoietic system.
Description of the Related Art
Recent progress in the field of gene therapy has raised the hope that patients afflicted with hemoglobinopathies such as β thalassemia and sickle cell anemia will benefit from novel therapeutic approaches. Transplantation of hematopoietic cells (HCs) modified with lentiviral vectors carrying the β-globin gene has resulted in long-term correction of several mouse models of hemoglobin disorders Imren et al., Proc Natl Acad Sci USA. 2002; 99(22):14380-14385; Malik et al., Ann NY Acad Sci. 2005; 1054:238-249; May et al., Nature. 2000; 406(6791):82-86; Pawliuk et al., Science. 2001; 294(5550): 2368-2371), but in contrast, has led to transfusion independency in only one β thalassemic patient (Cavazzana-Calvo et al., Nature. 2010; 467(7313):318-322). Although the main advantages of infusing genetically modified autologous cells are to avoid the risks of GVHD and immunosuppressive pretransplant conditioning as well as to address the lack of compatible donors, current therapy faces at least three substantive caveats: the requirement for toxic myeloablation (Dunbar et al., Hum Gene Ther. 1998; 9(17):2629-2640); current gene transfer methods are unable to transduce more than a fraction of hematopoietic stem cells (HSCs) (Santoni de Sio and Naldini, Methods Mol Biol. 2009; 506:59-70); and various in vivo selection strategies available suffer from suboptimal efficacy and safety (Beard et al., J Clin Invest. 2010; 120(7):2345-2354; Cornetta et al., Cancer Gene Ther. 2006; 13(9):886-895; Milsom et al., Cancer Res. 2008; 68(15): 6171-6180).
For example, β thalassemic recipient mice required at least 200 rads of irradiation and a very high dose of bone marrow cells (>20×106) to achieve stable engraftment and phenotypic improvement (Bradley et al., Biol Blood Marrow Transplant. 2002; 8(8):453-461. However, cytokine-expanded marrow cells have a defective long-term repopulating capability in irradiated (Peters et al., Blood. 1996; 87(1):30-37) as well as nonmyeloablated mouse recipients, (Ramshaw et al., Blood. 1995; 86(3):924-929) leading to low-level engraftment of retroviral transduced cells in mice and patients in the absence of a pretransplantation conditioning regimen (Dunbar et al., 1998; Kittler et al., Blood. 1997; 90(2):865-872).
Accordingly, there is a need in the art for improved methods of gene therapy for the treatment or prevention of hematopoietic disorders. The present invention offers solutions to these and other problems that plague the art.